1. Field of the Invention
The present invention relates to the discovery of molecules that inhibit an immune or inflammatory response in a subject. The present invention also relates to treating neurodegenerative disease. More specifically, the invention disclosed herein concerns molecules that interact with a FPR class receptor.
2. General Background and State of the Art
The formyl peptide receptor, FPR, class receptors are G-protein-coupled, seven transmembrane receptors that bind the chemoattractant fMLP and are involved in monocyte chemotaxis and the induction of a host immune response to a pathogen. The prototype FPR class receptor, FPR, binds fMLP with high affinity and is activated by low concentrations of fMLP. The binding of FPR by fMLP induces a cascade of G protein-mediated signaling events leading to phagocytic cell adhesion, chemotaxis, release of oxygen intermediates, enhanced phagocytosis and bacterial killing, as well as MAP kinase activation and gene transcription.
Formyl peptide receptor like 1 (FPRL1) is one of the classic chemoattractant receptors, i.e., a G protein-coupled seven trans-membrane receptor. FPRL1 was initially cloned as a formyl peptide receptor (FPR) homolog by low stringency hybridization with the human FPR cDNA probe (1). FPRL1 has 69% sequence identity at the amino acid level with FPR (1). Though FPR expression is restricted to phagocytic cells, FPRL1 is expressed in various cell types, including, phagocytes, epithelial cells, endothelial cells, hepatocytes, and astrocytoma cells (2-5). This broad spectrum of receptor expression indicates that FPRL1 may be involved in the regulation of various cellular responses. FPRL1 has important roles in the regulation of immune responses by modulating the activities of phagocytes (6). As member of a family of FPR that are capable of binding bacterial chemotactic formyl peptides, FPRL1 is regarded to perform a role in the host defense mechanism against pathogen infection (6, 7). In particular, FPRL1 has been reported to mediate phagocyte chemotaxis (8, 9), and the activation of FPRL1 was found to cause superoxide generation and exocytosis in human neutrophils. In terms of the modulation of HIV-1 infection, FPRL1 has been reported to attenuate HIV-1 infection by enhancing innate immunity, and its transition to adaptive immunity, or by desensitizing important chemokine receptors that act as co-receptors of viral infection (10). CCR5 and CXCR4 were desensitized by FPRL1 activation in a phosphorylation-dependent mechanism (10). FPRL1 plays a role not only in the immune system, but also in the neuronal system. FPRL1 has important implications in several disease states, such as in amyloidosis and in neurodegenerative disease (11, 12). FPRL1 was also found to be highly expressed in mononuclear phagocytes that infiltrate the brain tissues of Alzheimer's disease patients (12). FPRL1 is also believed to play a role in the pro-inflammatory aspects of prion disease (13).
Recently, several novel FPRL1 agonists have been identified. They include host-derived agonists, such as LL-37, an enzymatic cleavage fragment of the neutrophil granule-derived cathelicidin, and a mitochondrial peptide fragment MYFINILTL (SEQ ID NO:1) cleaved from NADH dehydrogenase subunit I (8, 14). Some peptides derived from HIV-1 envelope proteins have also been demonstrated to bind FPRL1 (15-17). Among peptides from gp41 of HIV-1, T21/DP107 was found to be a potent ligand for FPRL1 (15). Two different peptides from gp120 named F peptide and V3 peptide are also potent FPRL1 agonists (16, 17). From random peptide libraries Back et al., isolated a potent leukocyte stimulating peptide, Trp-Lys-Tyr-Met-Val-Met-CONH2 (WKYMVM, SEQ ID NO:2), Seo et al., modified by substituting the L-methionine at the C terminus of peptides with D-methionine to produce the more potent ligand, Trp-Lys-Tyr-Met-Val-D-Met-ONH2 (WKYMVm, SEQ ID NO:3) (18, 19). Recently Le et al. demonstrated that WKYMVm (SEQ ID NO:3) is a potent peptide ligand for FPRL1 (20).
For normal physiological responses, phagocytic cells must be recruited into sites of tissue damage. Recruited cells perform key roles against invading pathogens or to remove damaged cells. However, if the recruitment of phagocytic cells into the infection site is excessive, it causes several adverse effects, for example, tissue damage and inflammatory disease (21). Since most agonists induce many cellular signals that modulate complex cellular responses via binding to their specific cell surface receptors, the development of selective antagonists against specific receptors appears to be a sound approach for the generation of anti-inflammatory molecules. In terms of FPRL1, although the receptor plays a critical role in the recruitment of phagocytic cells into an infected area and several FPRL1 agonists have been reported, no antagonists for FPRL1 have been reported. To reveal the role of FPRL1 in physiological and pathological conditions specific FPRL1 antagonists would be highly desirable.